Perfluorooctane sulfonate induced ferritinophagy via detyrosinated alpha tubulin-TRIM21-HERC2-regulated NCOA4 degradation in hepatocytes

Abstract

The persistent organic pollutant perfluorooctane sulfonate (PFOS) is demonstrated to induce hepatotoxicity through disrupting iron homeostasis and subsequent ferroptosis in hepatocytes. However, it is still elusive in the mechanisms underneath the dysfunctional iron metabolism caused by PFOS. In this study, we observed that PFOS activated the nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy in mice liver and human hepatocytes. PFOS reduced the ubiquitination of NCOA4, subsequently causing an increase in the expression of NCOA4. PFOS induced the ubiquitination of HECT and RLD domain-containing E3 ubiquitin protein ligase 2 (HERC2), an upstream negative regulator of NCOA4, leading to the degradation of HERC2. PFOS upregulated the level of detyrosinated α-tubulin (detyr-α-tubulin) in hepatocytes. Under PFOS exposure, detyr-α-tubulin interacted with tripartite motif containing 21 (TRIM21), another E3 ubiquitin ligase responsible for HERC2 degradation. Despite the reduction in the protein level of HERC2, the increases in detyr-α-tubulin and the interaction between detyr-α-tubulin and TRIM21 caused by PFOS facilitated the interaction between TRIM21 and HERC2. Furthermore, inhibiting α-tubulin detyrosination by parthenolide reversed the ferritinophagy and the following ferroptosis caused by PFOS. Collectively, this study points out the existence of ferritinophagy and enriches the understanding of the alteration in iron metabolism under PFOS exposure, providing novel mechanistic insights into the hepatic toxicity of PFOS.

Keywords: Detyrosinated α-tubulin; Ferritinophagy; Ferroptosis; Perfluorooctane sulfonate; TRIM21.